Differentiation from na[unreadable]ve T helper (Th) cells into Th1 and Th2 subsets is an important process that determines the immune response to intracellular and or extracellular pathogens via the secretion of distinct cytokines. Transcription factors, c-Maf and GATA-3 direct Th2 lineage commitment, whereas T-bet, recently discovered in our laboratory, serves as a master regulator for Th1 cell differentiation (Reviewed by Ho & Glimcher, Cell 2002). Recent work suggests that dendritic cell (DC) subsets contribute significant polarizing influences on T helper differentiation. Outcomes of both innate and adaptive immune responses are directly related to the distinct profile of DC-derived cytokines. We have found recently that T-bet controls the production of the inflammatory cytokine IFNgamma from both marrow derived and splenic DCs. Thus, T-bet controls Th1 polarization both in T and NK cells as well as DCs, and acts as a master regulator of both innate and adaptive immune responses. However, the mechanisms by which T-bet controls Type I immunity in cells of the innate immune system are unknown. In the proposed studies, we will ask (i) what regulates T-bet expression in DCs (Specific Aim 1); (ii) what are the target genes for T-bet in DCs? (Specific Aim 2) and (iii) what are the functions of T-bet in DCs in the setting of pathological states (Specific Aim 3). These studies may permit the rational design of agents that manipulate the relevant signaling pathways, both in DCs as well as in Th cells, to enhance Type 1 immunity for infections, and to control inflammation, autoimmune diseases and other pathological states with much higher efficiency.